UA68328C2 - Delayed release formulation of paroxetine and method for treatment - Google Patents

Abstract

A controlled release or delayed release formulation contains a selective serotonin reuptake inhibitor (SSR_) such as paroxetine or its pharmaceutically acceptable salt. Such paroxetine formulation may be used for treating and preventing dystonia, alcohol addiction, obesity and others.

Description

Description of the invention

The basis of this invention is the preparation of a new composition, which includes paroxetine or 2 of its certain pharmaceutically acceptable salts, it is also about its use in the treatment and/or prevention of certain disorders.

US Patent No. 4,007,196 describes, among other things, a composition commonly known as Paroxetine. This composition is a Selective Serotonin Uptake Inhibitor (S5KI) and has recently become known on the world market as a means for the treatment and/or prevention of depression.

This is the only composition of paroxetine hydrochloride sold on the market - it is a tablet for parenteral use.

Recently, compositions of controlled action, as well as long-acting, containing paroxetine have been discovered; they surprisingly reduce the side effects typically associated with parenteral pills.

Thus, this invention provides an impetus for the emergence of compositions of controlled action, long-acting, containing 19 paroxetine and a certain pharmaceutically acceptable salt thereof.

Another aspect of the present invention are compositions of both controlled action and long-acting containing

ZOKI. The composition of ZOKI samples other than paroxetine include fluoxetine ("US Patent Mo4,314,0817"), fluvoxamine ("US Patent Mo4,085,225") and sertraline ("US Patent Mo4,536,518").

The term "composition of controlled action" is understood as any technical composition in which the action ("yield") of the active substance depending on the dosage can be changed to achieve the fastest action, than in cases with conventional parenteral tablets or capsules.

The term "long-acting composition" means any technical composition in which the output of the active substance, depending on the dosage, can be changed to extend the duration of action compared to cases with ordinary immediate-acting products. Further "release" of the active substance from the long-acting composition can also be controlled with 29, as mentioned above. Go)

Examples of controlled-release compositions that may include paroxetine and other C5KIs are described in: "Viviaipede KeYease Meadisayopv, Spetisa! Tespoiodu Kemiem. 177. Ey. 9U.S.doppzop. Mouez Oaa Sogrogayop 1980". "Sopigolea Ogyd Oeiiimegu, Eipaatepiaiz apa Arriisaiope, 2pa Eaiiop. dv. .K. Kobipzop, M.N. ee. so

Megsei Oekkez Ips. Mem/ Hogk 1987". p

Examples of long-acting compositions that may include paroxetine and other 55KIs are described in: "Ketipdiop'z

Rpagtaseciisa! Zsiepsev" 16(1p Ediop, Musk Rybiizpipd Sotrapu 1980, Ea. A. Ovoi". o

Such compositions of controlled action are composed primarily so that the release of the active substance, for example paroxetine, is carried out primarily during its passage through the stomach and small intestine, and long-acting compositions are composed primarily so that the release and action of the active substance, for example paroxetine, is carried out mainly during its passage through the small intestine, but not during the stay of the substance in the stomach.

The above-mentioned compositions are mainly calculated so that the duration of action of the active substance is 1.5-3 hours after use. "

In addition to the effect on the small intestine, the composition also affects the duodenum, ileum, and jejunum. This composition will be most useful for patients suffering from nausea after oral treatment with parenteral tablets.

From" The compositions offered by us at the end of the manufacturing cycle are coated tablets, tablets (capsules) coated with wax or polymers, or long-acting bases ("matrix"), or their combinations.

Some of these compositions are listed in US Patent No. 5,102,666.

Therefore, the task of the invention is to create a polymer composition of controlled action, containing a reactive b complex, which is formed by the interaction of (1) a component of calcium polycarbophil, which swells, but does not dissolve in water, a fibrous cross-linked carboxy functional polymer, and the indicated polymer contains (a) a plurality of repeating unit units, of which at least 8095 contain at least one carboxyl functionality, and (B) from about 0.595 to 1.596 of a cross-linking agent, entirely free from polyalkenyl polyester, such percentage being formed by the mass of unpolymerized repeating unit units, and cross-linked the combined agent according to (2) with water in the presence of an active co-agent selected from the group consisting of selective serotonin reuptake inhibitors

ZK, such as paroxetine. The amount of selected calcium polycarbophil may be between 0.195 and 9995 by weight, for example 1095. The amount of selected active agent may be between 0.000195 and 6595 by weight, 29 for example between 595 and 20905. The amount of water may be between 595 and 200905 by weight, for example 5-1095. Interaction

HF) is carried out at a pH that is approximately from 3 to 10, for example 6-7. Calcium polycarbophil in its natural state is in the form of its salt, which contains approximately 595 to 2595 calcium. o Further separately defined compositions are filed under US patent No. 5,422,123. Therefore, the next separate aspect of the present invention provides a system for controlling the action of the active substance, that is, one of the NSAIDs, such as 60 paroxetine, containing (a) a core with an effective amount of the active substance and having a certain geometric shape, and (B) an outer shell for the above core, where said core contains at least an active substance and at least one component selected from the group. This group consists of (1) a polymeric material that swells upon contact with water or water-like liquids, and a polymeric material that can turn into a gel. Here, the proportion of said polymer material that swells upon contact with water or water-like liquids and polymer material that can be converted into a gel will be in the range of 1:9 to 9:11. Also, the composition must include (2) one polymeric material with a combination of both swelling and gelling properties, where the outer shell is an elastic support shell. It partially covers the mentioned core and gradually changes under the action of hydration of the core, in a slow way

Formation and/or gelation in aqueous liquids. The outer shell may contain polymers such as, for example, hydroxypropyl methylcellulose, plasticizers such as glycerides, binders such as polyvinylpyrrolidones, hydrophilic agents such as lactose and silicas, and/or hydrophobic agents such as manganese stearate and glycerides . Polymers, as a rule, make up 30-9095 of the weight of the outer shell, for example about 35-40956. Plasticizers can be at least 295% of the weight of the outer shell, such as 76% of about 15-2095. Binders, hydrophilic agents, and hydrophobic agents typically comprise about 5095% of the weight of the outer shell, for example, about 40-50905%.

The paroxetine used in this project is used in the form of the free base or its pharmaceutically acceptable salt. In most cases, paroxetine is used in the form of hydrochloride hemihydrate.

Parotexin hydrochloride hemihydrate can be prepared according to the method described in U.S. Pat

Mo4,721,723.

Paroxetine in the form of a controlled-release formulation or a long-acting formulation can be used to treat and prevent the following disorders:

Alcoholism.

Phobias, state of anxiety.

Depression.

Obsessive compulsive disorders.

Panic disorders.

Chronic pain. with

Adiposity.

Senile dementia. Migraine. and)

bulimia

Anorexia

Social phobia. Premenstrual syndrome (PMS).

Teenage depression. with

Trichotillomania. with

Dysthymia.

Substance abuse. co

All these diseases will be referred to as "(these) disorders". "at

The present invention provides a method for the treatment and/or prevention of these disorders by administering to the patient, if necessary, an effective therapeutic or prophylactic dose of a composition of controlled or prolonged action, which contains paroxetine or a certain pharmaceutically acceptable salt thereof.

In particular, this invention also considers the aspect of using a composition of controlled action or a composition of "prolonged action with paroxetine or a certain pharmaceutically acceptable salt thereof for the treatment and/or prevention of these disorders.

The invention also covers pharmaceutical compositions of controlled action and long-acting compositions containing;" paroxetine or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of these disorders.

Below are examples for illustration:

Example 1. (Hydrophilic base) (22) so s yuyu

Ektratanyutyuana zastia so vv (F. Example 2. (Hydrophilic base) ko - bo

Ectratanuated stasis

My

Lactose 39.0

TOTAL 100.0

Example C (Sensitive pH coating of the core of the instant-acting composition)

The core of the pill

Paroxetine hydrochloride 11.45 70 Microcrystalline cellulose 100.0

Tablet coating (contains approximately 6-1095 weight of tablet core).

Hydroxypropylmethylcellulose 90.0

Triacetin 10.0

Example 4. (Instant acting pH sensitive core coating) The tablet coating composition is similar to Example 3. Tablet coating (containing approximately 6-1095 weight of tablet core).

Acetate phthalate cellulose 90.0 diethyl phthalate 10.0

Example 5. (Covering of the controlled action of the instantaneous action core) o

The tablet coating composition is similar to example 3.

Tablet coating (contains approximately 5-1295 weight of tablet core).

Eudragit KZ 100 86.0 so dibutyl phthalate 10.0 talc 4 s

ROS, yellow, Mob 0.01 so

Example 6. (Sensitive pH coating of the core of controlled action) (ee)

Composition for the core of the tablet - as in example 3. so

Tablet coating composition - as in example 3.

Tablet coating (approximately 6-1095 of the weight of the tablet core).

Cellulose acetate phthalate 90.0 " diethyl phthalate 10.0 - s Example 7. (Coated dragees of controlled action, in capsules). and? : d -

Irregular granules

Paroxetine hydrochloride

F Zhelyamno 171118 so o poditya ka 20 Glyceryl monostearate

Glyceryl distearate so

Example 8. (Double-layer tablets of controlled action) o co Paroxetine hydrochloride 22.897

Metocel KAM 15.00 Hydrogel polymer b5 Components. mg/tab Functions

Total weight of Pvavemi tablets

The powder mixture for each layer was wet granulated through a high shear mixer/granulator and dried in a fluidized bed dryer. Then the two-layer tablets were compressed on a three-layer compression press of the Manesti company.

Example 9. (Enterally coated calcium polycarbophil composition)

Paint spraying, bezel LU 11 so with 5 F

Each core component was granulated in a wet environment through a mixer/granulator with a large "

By shear force and dried in a dryer with a layer of boiling liquid. After addition of manganese stearate, process - c continued in a low shear mixer. After that, the mixture was compressed on a rotary compression press of type B. The coating technology was performed using Asseyia soya. "» Example 10. (Double-layer tablets of controlled action) 15

Ф со с Lyuozymonehydrate | 800 Pdroflniatnt i. with so o t bo

Zatalnavagataeteti ele 0 65 For further processes, see in example 8.

Example 11. Two-layer tablets of controlled action)

and about

Zatalnazatatayelets waye!

Outer shell as in example 10.

Further processes are in example 8.

Example 12. Enterally coated tablets of controlled action) 2 сх ж о со з се не со з Ф " 2 2 s Zatalnavatatayelety sem 1 . with

Further processes - see in example 9. (is) Example 13,

Study of possible deviations (extremely acceptable side effects) for the gastrointestinal tract when taking drugs. (9) The outline of the study project is proposed below.

Participants of the experiment: volunteers with a satisfactory state of health. o Project: Parallel group, placebo-controlled, "doibie Biip" method ("double blind").

IR f) Treatment: (a) placebo, (b) immediate-release paroxetine, (c) composition of Example 8, (4) composition of Example 8 with enteral coating.

Dosage: ZOmg daily, once for 3 days.

Number of participants in the experiment: 452 for the medical examination (488 by the method of blind selection, 485 for the medical examination).

IF) A study was conducted on the incidence, extent and duration of nausea, vomiting and diarrhea (theoretically, if the compositions of controlled action slow down the absorption of paroxetine, then, since paroxetine is considered a prokinetic for the gastrointestinal tract, we can talk about an increase in the level of morbidity). 60 Information on adverse factors (AIF) was studied and assessed every morning during medication use and 24 hours after the last dose. Experts and participants of the experiment were offered diary cards for the classification of INF strength in order to standardize them as clearly as possible in all the centers of the experiment.

Among 485 individuals selected for medical review, 18(3,790) discontinued their participation, 17 of them due to 65 adverse effects. Individuals who stopped participating were more likely to be in group (B) than in (c) or (4) on the day the experiment ended.

Cases of nausea or vomiting and diarrhea are presented in the table below (in 90): t placeso, nausea, diarrhea

Cases of nausea increased for both (B) and placebo compared to the expected norms by approximately 2590 and 70, respectively, by 595 for volunteers at these dosages for 3 days. The overall incidence of nausea was lower among (a) than among (B). The strength of the nausea also decreased, as shown in the following table: сяенуют в | 615 placebo!

The strength of diarrhea is shown in the table

Tjazhestdere| | 619 placebo! school in o

Thus, it was found that there was a tendency to decrease the incidence of nausea and cases of discontinuation of experiments due to an adverse effect, if compared with (B), but the analysis was complicated by a significant difference in the directions of treatment methods, (4) demonstrates a decrease in the rate of discontinuation of experiments by 50905, and with a decrease in the incidence of nausea - by 2095 (when according to the proportion it should be 33905). In addition, the strength of nausea in persons among (c) and (4) decreases. An increase in diarrheal diseases was observed among (c) and (4) In c compared to (B), but here we are talking about an increase in diarrheal diseases of medium strength, however, among the participants of the experiment, complaints about the growth of diarrheal diseases of significant strength were not found. with

Claims (4)

The formula of the invention ise) 1. A composition of controlled and long-term action, which differs in that it is adapted or intended for oral administration and contains a selective serotonin uptake inhibitor ("S5KI"), which is paroxetine or " and its pharmaceutically acceptable salt. -at 2. The composition according to claim 1, which differs in that it is an enteric-coated tablet or pill, a wax- or polymer-coated tablet or pill, or a sustained-release matrix. :z» Z. The composition according to claims 1 or 2, which differs in that it is a polymer composition of controlled action, containing a reaction complex that is formed by the interaction 1. a calcium polycarbophil component that swells but does not dissolve in water, a fibrous cross-linked 395 carboxy functional polymer, and the specified polymer contains Ф (a) a set of repeating chain elements, of which at least 8095 contain at least one carboxyl (ee) functionality, and c | (5) from 0.7 to 1.596 of a cross-linked agent substantially free of the polyalkenyl polyester, said percentage being formed by the weight of unpolymerized repeating unit elements and cross-linked to 50 of the cross-linked agent, respectively, with 2. water in the presence of an active agent selected from group, which in turn consists of selective inhibitors of serotonin absorption ("ZK"). 4. The composition according to any one of claims 1-3, which is characterized by the fact that it is a system for the controlled release of an active substance, which is "55", which contains 59 (a) a core with an effective amount of an active substance and has a defined geometric shape, and GF) (c) an outer shell for said core, wherein said core contains at least one active substance and at least one component selected from the group consisting of 1. a polymeric material that swells upon contact with water or water-like liquids and a polymeric material that can turn into a gel, and the ratio of said polymeric material that swells upon contact with water or water-like liquids and polymeric material that can turn into gel, is from 1:9 to 9:1, and 2. one polymeric material that has swelling and gelling properties, where the outer shell is elastic and intended to partially cover said core, which gradually changes under the action of hydration of the core through slow dissolution and/or gelation in aqueous liquids. because 5. A method of treatment and/or prevention of such disorders as alcoholism, phobias, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, substance abuse, which differs in that the patient prescribe a therapeutic or prophylactic dose of a composition of controlled or long-term action according to any of claims 1-4. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 8, 15.08.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 6) (ee) s (ze) (ee) (Se) - with . and? (o) (ee) (95) with 50 IR e) ime) 60 b5